Gastric cancer is the second most common cause of cancer-related deaths worldwide. There is growing evidence suggesting that cancer signaling networks are wired in a complex manner. This complexity is translated into poor clinical outcome, a common feature of gastric cancer. This wiring is not only important for maintaining cancer cell survival but also for providing supportive properties such as angiogenesis. The molecular targets that govern this interaction between the molecular signaling pathways that drive gastric tumorigenesis remain largely uncharacterized. Therefore, the identification of critical molecular targets, located at the hub of the signaling networks that bridge cancer signaling pathways, is a key step in understanding the biology of gastric cancer and improving our currently limited diagnostic, preventive, and therapeutic approaches. In the present proposal, we plan to pursue our novel finding that shows DARPP-32 at the interface of two key signaling pathways, NF-kB and STAT-3; thus playing a crucial role in the development and progression of the gastric tumorigenesis cascade. The proposal examines a novel hypothesis that transcription up-regulation of DARPP-32 by NF-kB connects cancer cell signaling pathways leading to activation of STAT3, thereby placing DARPP-32 as a bridge between two important signaling pathways amplifying their oncogenic signals promoting angiogenesis and tumorigenesis. We propose three specific aims to test our hypothesis. The first aim will test the transcription regulation of DARPP-32 by NF-kB and examine the mechanisms by which DARPP-32 regulates STAT3 signaling. These studies will define the role of DARPP-32 as a bridge between two important oncogenic signaling pathways, NF-kB and STAT3. In Aim 2, we will examine the biological outcome of the NF-kB - DARPP-32 - STAT3 axis, explore its role in regulating angiogenesis, and determine the therapeutic potential of targeting the DARPP-32 signaling axis. The third aim, will determine the role of DARPP-32 in promoting gastric tumorigenesis using genetic mouse models of DARPP-32 overexpression and knockdown. We will also explore the histopathological and clinical significance of overexpression of NF-kB - DARPP-32 - STAT3 in fully annotated de-identified human gastric cancer tissue samples. Our studies are conceptually innovative and of critical significance given the fact that the overall 5-year survival for gastric cancer is only 20%. Upon completion of our studies, the results will have a significant impact on understanding the biology of gastric cancer affecting our diagnostic, prognostic, and possibly clinical management of this disease.